Rare Cases of Immune Failure With HIV Suppression

In the overwhelming majority of cases of HIV, adhering to a regimen of antiretroviral therapy (ART) effectively suppresses viral levels in the body. This standard of care allows the level of CD4+ T cells to bounce back to normal. In some patients with HIV, the CD4+ T cells never become fully restored. These so-called immunological nonresponders (INRs) have higher mortality rates than other individuals on ART. However, an even more dramatic immune decline may occur in a handful of few patients, who not only do not gain CD4+ T cells but actually lose them after being on ART.

A team of investigators at the National Institutes of Health’s (NIH) National Institute of Allergy and Infectious Diseases (NAIAD) reported on 5 individuals with HIV who experienced this dramatic decline in CD4+ T cells even though they were on ART. Individuals with this extreme immune decline (EXID) experienced a median CD4+ decrease of 157 cells/ul after being on ART for 192 weeks straight. This is in comparison to INRs, who had a median CD4+ increase of 193 cells/ul, and immunological responders, who saw a median CD4+ increase of 427 cells/ul.

The patients, who were referred to the NIH Clinical Center after going through extensive workups revealing no malignancies, ranged in age from 13 to 49 years. Interestingly, all of them were infected with non B-type HIV, which is the most common strain in North America and Europe. Because no subjects had the HIV subtypes typically circulating in these places, the investigators believe their responses to ART may have something to do with an interaction between the specific HIV type carried and the subjects’ own genes.

“Those are patients that are clearly responding in a different way,” Andrea Lisco, MD, PhD, assistant clinical investigator at NIH Clinical Center and an author of the study, told Contagion®. “[We think it has to do with] some particular genetic makeup of the host.” These genetic factors, in combination with specific viral factors, resulted in the atypical result of extreme immunological decline.

Confounding the issue is that the 5 subjects with EXID in this study did not all experience this inflammatory decline in the same way. One subject who was followed up long term was revealed to have an orbital inflammatory disorder which, when it was treated with infliximab, resulted in the restoration of the CD4+ T cells. Two others experienced inflammation while 2 exhibited symptoms suggestive of autoimmunity.

It’s possible that, if there is underlying inflammatory disease in addition to HIV, treating the underlying disease may result in rising CD4+ T levels in people who have EXID. “We believe that if we’re able to find ways to control the exuberant inflammation, we can recover the CD4 count in the subset of patients in which we see exuberant inflammation,” Lisco said.

For others, the answer may simply be to do nothing. “If the patient is clinically stable, even if the CD4+ count is at the lower end, we probably can just watch and monitor,” Lisco said.

As for how many people with HIV have EXID, Lisco and his team feel they are most likely exceedingly rare, having received reports of these 5 subjects over a period of 10 to 15 years. “We’ll have to see how common this problem is,” he said. “I hope it’s going to be extremely limited.”